Acute pancreatitis is a multi-faceted disease that is associated with considerable morbidity and mortality. In the United States alone, more than 300,000 patients are hospitalized annually with pancreatitis. Lung, kidney, and heart failure may all occur in severe cases. Pancreatitis is a primary factor in about 3,200 deaths, and a contributing factor in about 4,000 additional deaths, annually. Direct costs attributable to pancreatitis top $2 billion annually. See, e.g., Saluja and Bhagat, Gastroenterology, 124(3):844-847 (2003).
Conventional wisdom states that pancreatitis begins with the intra-pancreatic activation of digestive enzyme zymogens, acinar cell injury, and activation of transcription factors such as Nuclear Factor Kappa B (NF-κB) and Activator Protein-1 (AP-1). This is followed by a proinflammatory cascade leading to acinar cell necrosis, systemic inflammatory response syndrome (SIRS) and distant organ dysfunction including lung injury that frequently manifests as the acute respiratory distress syndrome (ARDS). Ultimately, the severity of acute pancreatitis depends upon the extent of systemic inflammatory responses.
The Toll-Like Receptors, or “TLRs,” are named for their structural and functional homology to a receptor found in the Drosophila fruit fly, named TOLL. In humans, TLRs play an important role in activating an innate immune response to pathogen-related molecules, and hence are also known as pattern recognition receptors (PRR's). Over ten members of the TLR family have been identified in the human and mouse, designated as TLR2, TLR4, TLR5, and so on, each receptor recognizing a small range of conserved molecules from a group of pathogens. TLRs are expressed on monocytes, macrophages, dendritic cells, lymphocytes and in other cell lines, including vascular endothelial cells, lung and intestinal epithelial cells, cardiac myocytes, and adipocytes.
TLR4 is perhaps the best characterized member of this family of receptors. It binds to lipopolysaccharide (LPS) as well as to a number of host protein molecules that are released at sites of damage and infection. TLR4 is a type I transmembrane protein with extracellular domains containing leucine-rich repeats that may participate in ligand recognition. The intracellular domains contain regions that are highly homologous to the intracellular domain of the IL-1R, and these regions are referred to as Toll/IL-1R (TIR) domains. The intracellular signaling pathway is known to activate mainly the NF-κB transcription factor, which, in turn, triggers the expression of many pro-inflammatory cytokines such as TNF-alpha, IL-1beta, IL-6, and IL-8, and leads to maturation of antigen-presenting cells.